Age-related macular degeneration (AMD) is the most devastating ocular neurodegenerative disorder that accounts for approximately 50% of all blindness cases in the United States and other developed nations. Three major pathological factors of its most catastrophic neovascular (wet) form include local inflammation with hypercytokinemia and retinal infiltration with immune cells, uncontrolled neovascular growth of choroidal blood vessels penetrating the retina and retinal vascular leakage that leads to degeneration of photoreceptors. All the above processes are orchestrated by pro-inflammatory/pro-angiogenic cytokines including VEGF as one of the major players. The standard-of-care anti-VEGF biologics delivered intravitreally improve visual acuity in less than half of the patient population. Both certain degree of functional redundancy between VEGF and other cytokines and poor anti-inflammatory efficacy of VEGF-blockers due to compensatory elevations in leukocyte infiltration are among the key factors that apparently account for the high proportion of non-responders. The new therapeutic approach we propose is aimed to improve both therapeutic responsiveness and drug delivery mode. The small GTPase Arf6 has been extensively validated as a promising drug target that, by virtue of its central role in destabilizig interendothelial adherens junctions, is prominently involved in promoting cytokine-mediated vascular hyperpermeability, angiogenesis and immune response. The relevant potential advantages of Arf6 over VEGF include i) its position at a convergence point of multiple cytokine signaling pathways that are associated with AMD pathogenesis; ii) demonstrated involvement in control of cytokine- mediated vascular permeability but not cytokine synthesis that opens a possibility to manage inflammation by directly targeting leukocyte infiltration while still avoidin global immunosuppression; iii) druggability with small molecules that are potentially amenable to non-invasive delivery. A first-in-class structural series of small molecule Arf6 inhibitors with demonstrated low micromolar potency, mechanistic tractability, nascent SAR, selectivity over a panel of other GTPases as well as efficacy in cellular models and, most importantly, in two mouse models of neovascular AMD has been found in HTS. Top compounds are proposed as starting point for the medicinal chemistry optimization that is aimed at development of a novel retinal neuroprotective drug candidate in collaboration with the NIH Blueprint Neurotherapeutics Network.